Tetrahydrofuran → 1-((2-(7-fluoro-1H-indol-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amine

HRID 1692884Notes

Reaction equation

HRID 1692884 reaction equation
[CH3:1][N:2]([CH3:38])[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([Sn](CCCC)(CCCC)CCCC)=[N:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4]1.C1(S([N:48]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][C:55]=3[F:57])[C:50](Br)=[CH:49]2)(=O)=O)C=CC=CC=1.C1COCC1.[OH-].[Na+]>C(O)C.S1C=CC=C1C([O-])=O.[Cu+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:57][C:55]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:56]=1[NH:48][CH:49]=[C:50]2[C:14]1[N:15]=[C:16]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:17]2[S:18][C:10]([CH2:9][N:6]3[CH2:7][CH2:8][CH:3]([N:2]([CH3:38])[CH3:1])[CH2:4][CH2:5]3)=[CH:11][C:12]=2[N:13]=1

Participants

8

Reactant 4

HCID 8028TetrahydrofuranHCID 14798Sodium HydroxideHCID 596035291-benzenesulfonyl-3-bromo-7-fluoro-1H-indoleHCID 59605498Dimethyl-[1-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperidin-4-yl]amine

Product 1

HCID 596034151-((2-(7-fluoro-1H-indol-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amine

Reagents, catalysts & solvents 3

HCID 11194830Cuprous 2-thiophenecarboxylateCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 702EthanolSolvent

Procedure

To a mixture of dimethyl-[1-(4-morpholin-4-yl-2-tributylstannanyl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-amine (250 mg, 0.396 mmol), 1-benzenesulfonyl-3-bromo-7-fluoro-1H-indole (163 mg, 0.460 mmol), copper(I) thiophene-2-carboxylate (37 mg, 0.19 mmol), and Pd(PPh3)4 (44 mg, 0.038 mmol) was added THF (2 mL). The reaction vessel was evacuated and back filled with argon. The reaction mixture was diluted with hexane, filtered through a plug of solka floc, and the filtrate was concentrated. The residue was triturated with hexane and then purified by flash chromatography (silica, 0-10% MeOH/NH4OH (9:1) in DCM). The elutant was then concentrated to give an off-white solid which was taken up in ethanol (2 mL). A 1 M aqueous NaOH solution (0.25 mL) was then added and the resulting mixture was stirred at reflux for 2 hours. The reaction mixture was concentrated and triturated with water. The crude product was purified by flash chromatography (silica, 0-10% MeOH/NH4OH (9:1) in DCM) to give 118 as an off white solid (41.5 mg, 30%). LCMS: M+H+=495. 1H-NMR (300 MHz, DMSO-d6): δ 12.1 (s, 1H), 8.38 (d, 1H), 8.19 (d, 1H), 7.32 (s, 1H), 7.08 (m, 1H), 6.98 (m, 1H), 3.96 (m, 4H), 3.81 (m, 6H), 2.93 (d, 2H), 2.16 (s, 6H), 2.05 (t, 3H), 1.72 (d, 2H), 1.40 (m, 2H)

Workup

  1. customThe reaction vessel was evacuated
  2. additionback filled with argon
  3. additionThe reaction mixture was diluted with hexane
  4. filtrationfiltered through a plug of solka floc
  5. concentrationthe filtrate was concentrated
  6. customThe residue was triturated with hexane
  7. custompurified by flash chromatography (silica, 0-10% MeOH/NH4OH (9:1) in DCM)
  8. concentrationThe elutant was then concentrated
  9. customto give an off-white solid which
  10. temperatureat reflux for 2 hours
  11. concentrationThe reaction mixture was concentrated
  12. customtriturated with water
  13. customThe crude product was purified by flash chromatography (silica, 0-10% MeOH/NH4OH (9:1) in DCM)

Sources & evidence

ORD record
ord-f06cebdc3c9e44d892023694bc78dff2
Source dataset
uspto-grants-2012_04
Patent number
US08158625B2

Reaction notes

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